Development of suppressor tRNA-based therapeutics

Research Project information

Principal researcher: Professor Zoya Ignatova (University of Hamburg) and Professor Grant Stewart (University of Birmingham)
Institute:   University of Hamburg and University of Birmingham
Cost: £249,615 over 24 months in partnership with NATA (Nucleic Acid Therapy Accelerator), Oxford

Start Date: 1st of June 2024

What are the researchers proposing to do?
The underlying cause of Ataxia-Telangiectasia (A-T) is mutations in the ATM gene. Approximately 14% of A-T patients carry nonsense mutations (NSM, also known as premature stop mutations) in the ATM gene. All genes, including ATM, have natural signals called stop codons located at the end of the gene, which tells the tRNAs, which function to read the gene sequence and convert it to a protein, to stop adding amino acids onto the amino acid chain that makes up each protein. The presence of a nonsense mutation that introduces a stop signal before the end of the gene will result in the ATM protein produced being too short and lacking important regions necessary for its activity.

To counteract the presence of these nonsense mutations or premature stop signals, the researchers have developed specialised tRNAs, called suppressor tRNAs or sup-tRNAs, that specifically recognize individual premature stop mutations, which instead of halting protein production will allow protein production to continue to the end of the gene. This will allow full length ATM to re-expressed in cells, which they hope will prevent further damage caused by not having any ATM protein.

NSM are among the most devastating mutations and difficult to treat. Attempts to restore protein production with small molecule drugs are inefficient and cause many side effects at the natural stop codons. Sup-tRNAs are specifically tailored to each premature stop mutation, which they hope will precisely restore the ATM protein production by bypassing the NSM without any observable effects at natural stop codons.

How will the research be done?
The team will first test the efficacy of individual sup-tRNAs to bypass specific NSMs in the ATM gene and produce full-length ATM protein using patient-derived cell lines. Successful sup-tRNA that restore sufficient levels of ATM will be encapsulated in engineered viral-like particles, that are non-infectious but utilize the natural ability of viruses to enter the cells of the human body. Following validation of the ability of individual sup-tRNAs to restore ATM protein production in brain organoids (laboratory grown brains), the researchers will examine the safety of these viral-like particles using animal models.

How could it make a difference to the lives of those affected by A-T?
Depending on the efficacy of specific sup-tRNAs to bypass specific NSMs in the ATM and their ability to administer them efficiently to organs that are particularly susceptible to loss of ATM e.g. the cerebellum of the brain, it is possible that this therapy could potentially slow or halt progression of the neurological decline.